No association of the tryptophan hydroxylase gene with bipolar affective disorder, unipolar affective disorder, or suicidal behaviour in major affective disorder.

Tryptophan hydroxylase (TPH) is the rate-limiting enzyme in the synthesis of 5-hydroxytryptamine (5-HT). An association study in bipolar affective disorder I or unipolar major affective disorder was performed by using a Bfa I restriction site polymorphism within intron 7 of the tryptophan hydroxylase gene. A total of 118 bipolar, 125 unipolar, and 437 control subjects were used in the study (1:3.7 bipolar:control, 1:3.5 unipolar:control). There were no significant differences in TPH allele or genotype frequencies between the affective disorder and control groups. In addition, bipolar and/or unipolar subjects with or without a history of suicide attempts were compared for the TPH polymorphism. No significant differences were found between suicidal and non-suicidal groups in major affective disorder, in contrast to a previous study suggesting an association of this polymorphism with a history of suicide attempts among alcoholic violent offenders.

Analysis of the monoamine oxidase A (MAOA) gene in bipolar affective disorder by association studies, meta-analyses, and sequencing of the promoter.

Monoamine oxidases catalyse the oxidative degradation of biogenic amines including neurotransmitters such as noradrenaline, dopamine, and 5-hydroxytryptamine (5-HT). Three groups have reported positive associations of the monoamine oxidase A (MAOA) gene with bipolar affective disorder although other studies have been negative. In an extension of a previous study [Rubinsztein et al., 1996: Human Molec Genet 5:779-782] we report association studies of MAOA polymorphic markers and affective disorders. The polymorphisms comprised a CA-repeat microsatellite in intron 2 and a Fnu4HI G/T silent polymorphism at position 941 of the cDNA sequence. No significant differences were found when the control allele frequencies were compared with those in bipolar, unipolar, or combined bipolar + unipolar groups. Meta-analyses were then performed to include the data of all published studies using the MAOA microsatellite and Fnu4HI polymorphisms. Separate meta-analyses were performed for Caucasian and Japanese studies, as allele frequencies of the microsatellite in these populations were markedly different. Associations of bipolar affective disorder in pooled male and female groups were found with the MAOA microsatellite in both the Caucasian (P < 0.02) and the Japanese (P < 0.02) meta-analyses. In view of these positive associations, and as previous results have shown that coding variants do not account for the normal population variation in MAOA activity, over 1,300 bp of the promoter were sequenced in 22 bipolar cases and 1 control. A novel polymorphic promoter variable number of tandem repeats (VNTR) located approximately 1,200 bp upstream from the translation start site was demonstrated. However, there was no association of this promoter VNTR with affective disorder. These results suggest that there may be functional variants in other regions of the MAOA gene or neighbouring genes that affect bipolar affective disorder risk.

Genetic associations with clinical characteristics in bipolar affective disorder and recurrent unipolar depressive disorder.

Genetic factors may be associated with disease subtype as well as susceptibility. We have therefore typed polymorphisms at the serotonin transporter, dopamine receptor, tryptophan hydroxylase, tyrosine hydoxylase, and monoamine oxidase A (MAOA) loci in 139 unipolar and 131 bipolar patients and investigated associations with gender, number of episodes, age of onset, history of psychotic symptoms, history of suicidal behavior, and history of substance abuse. In bipolar subjects, the promoter variable number tandem repeat (VNTR) allele 132 of MAOA was associated with history of suicide attempts, P = 0.029, particularly in females, P = 0.006. The Fnu4HI allele 1 of MAOA was also associated with history of suicide attempts in females, P = 0.0162. The serotonin transporter promoter allele 2 was associated with increasing number of manic episodes, P = 0.02, and history of psychotic symptoms, P = 0.0243. One significant association was found in the unipolar group: dopamine D2 receptor promoter allele 2 with history of psychotic symptoms, P = 0. 0165. We have tested multiple loci for a variety of different clinical variables and performed 228 tests of significance in total. It is possible that these preliminary findings are type 1 errors, because one would expect 11 of the 228 tests to reach a nominal significance level of P < 0.05 by chance alone if all the tests were independent. The associations with the MAOA and serotonin transporter loci are consistent with previous data suggesting associations with susceptibility to bipolar affective disorder. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:36-42, 2000

Analysis and meta-analysis of two serotonin transporter gene polymorphisms in bipolar and unipolar affective disorders.

The serotonin transporter is a compelling candidate gene to examine in bipolar and unipolar affective disorder, since drugs that specifically inhibit the serotonin transporter can successfully treat depression. Previous association studies of a VNTR polymorphism in intron 2 and a functional insertion/deletion polymorphism in the promoter of this gene have produced conflicting results. The present study examined allele and genotype frequencies for both of these polymorphisms and resulting haplotypes in 87 English Caucasian bipolar patients, 125 English Caucasian unipolar affective disorder patients, and 174 controls. No significant associations were detected when these unipolar or bipolar cases were compared either separately or as a pooled "affective disorder" group to the controls. A meta-analysis of over 1,400 individuals of European Caucasian origin was then performed, comprising 772 controls, 375 bipolar and 299 unipolar patients for the VNTR polymorphism, and 739 controls, 392 bipolar and 275 unipolar patients for the promoter polymorphism. A significant association of promoter allele 2 was shown with bipolar (estimated odds ratio 1.21; 95% confidence interval 1.00-1.45), unipolar (OR 1.23; 95% CI 1.01-1.42), and combined bipolar + unipolar groups (OR 1.22; 95% CI 1.04-1.42). There was no demonstrable allelic association of the VNTR polymorphism with affective disorder: for the combined bipolar + unipolar group the odds ratios for VNTR alleles 9 and 10, compared with the common allele 12 were 1.05 (95% CI 0.56-1.95) and 0.90 (95% CI 0.77-1.05). These results suggest that the promoter allele 2, which has previously been shown to result in lower levels of serotonin transporter transcription, may be associated with affective disorder risk.

No association of a functional polymorphism in the dopamine D2 receptor promoter region with bipolar or unipolar affective disorders.

The dopaminergic system, along with the serotonergic and noradrenergic systems, has been implicated in the etiology of mood disorders. An association study of a functional variant in the promoter region of the dopamine D2 receptor (DRD2) with bipolar affective disorder I or unipolar major affective disorders was performed. Variable expression of the DRD2 gene in vitro has been shown with this promoter polymorphism. One hundred and thirty-one unrelated bipolar patients, 128 unrelated unipolar patients, and 262 controls were used in the study. There were no significant differences in DRD2 allele or genotype frequencies between the affective disorder and control groups. These results do not support a major role for the DRD2 gene in the etiology of either bipolar or unipolar affective disorders.

No association of an insertion/deletion polymorphism in the angiotensin I converting enzyme gene with bipolar or unipolar affective disorders.

A recent Japanese study on the angiotensin I converting enzyme gene (ACE) insertion/deletion polymorphism reported that both the D allele (P < 0.02) and the DD genotype (P < 0.002) were significantly more frequent in affective disorder cases than in controls [Arinami et al., 1996: Biol Psychiatry 40:1122-1127]. A replication study was performed by using 157 bipolar I affective disorder cases, 169 major depressive disorder cases, and 313 controls. No significant association with this polymorphism was found in either disorder or in a combined affective disorder group. These results do not support the ACE gene having a major role in the etiology of either bipolar or unipolar affective disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:733-735, 2000.

Analysis and metaanalysis of two polymorphisms within the tyrosine hydroxylase gene in bipolar and unipolar affective disorders.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine and noradrenaline. While positive associations between TH and bipolar affective disorder have been found in several studies, many studies have failed to reproduce these results. In order to clarify this situation, association studies of bipolar and unipolar affective disorder groups and metaanalyses of published data on the TH tetranucleotide repeat polymorphism were done. The association studies used the TH tetranucleotide repeat polymorphism in intron 1 and a PstI polymorphism at the 3' end of the gene. The study comprised 124 unrelated bipolar patients, 126 unipolar patients, and 242 controls. There was no significant association of either bipolar or unipolar affective disorder with the TH tetranucleotide repeat polymorphism. However, a weak association (chi2 = 3.946, 1 df, P = 0.047; odds ratio, allele 2 vs. allele 1 = 0.71 (95% CI, 0.51-0.996)) was observed in the unipolar sample with the TH-PstI polymorphism. Three metaanalyses of published data on the TH tetranucleotide repeat polymorphism in major affective disorder were performed: bipolar I + II vs. control using 583 cases and 745 controls; unipolar vs. control using 204 cases and 359 controls; and bipolar + unipolar vs. control using 846 cases and 823 controls. In each analysis there was no association of the TH tetranucleotide repeat polymorphism and affective disorder. These results do not support the tyrosine hydroxylase gene having a major role in the etiology of bipolar affective disorder. However, our data suggest that this locus should be examined in larger samples of unipolar affective disorder.

Acute dietary tryptophan depletion impairs maintenance of "affective set" and delayed visual recognition in healthy volunteers.

RATIONALE: Altered serotonergic transmission in affective disorders and Alzheimer's disease has prompted research aimed at defining the precise cognitive effects of depleting central serotonin in humans, using acute dietary tryptophan depletion. OBJECTIVE: We examined the effects of tryptophan depletion on mood and cognition in healthy volunteers. Cognitive tests of memory and attentional processing were employed to test hypotheses of central 5-hydroxytryptamine (5-HT) function related to cortical processing. METHODS: A double-blind, parallel design, placebo control study was employed with 15 subjects in each group. Mood rating scales were performed at the start and 5 h after ingestion of the drink. Cognitive tests were also performed at 5 h, after completion of the subjective rating scales. RESULTS: A robust reduction in total tryptophan was achieved in the test group. Subjects receiving the placebo drink showed the expected effect of shift on the affective shifting task, that is, more errors in the more difficult shift versus the non-shift condition. The tryptophan-depleted group made a similar number of errors in the shift trials but failed to reduce the number of errors in the non-shift trials. The tryptophan-depleted group showed a significant impairment on the delayed pattern recognition task. No significant effects on the subjective mood measures were found. CONCLUSIONS: Tryptophan depletion abolished the normal tendency to improve error scores on non-shift trials in response to affective cues on a go/no-go task. We suggest that this inability to "maintain set" in the non-shift condition may be due to a disruption of semantic retrieval processes concerned with affect. The novel finding of impairment on a delayed visual pattern recognition task confirms and extends previous studies where selective effects on memory and learning have been found following acute tryptophan depletion.

Selective attention to emotional stimuli in a verbal go/no-go task: an fMRI study.

Tasks requiring subjects to attend emotional attributes of words have been used to study mood-congruent information processing biases in anxiety and affective disorders. In this study we adapted an emotional go/no-go task, for use with fMRI to assess the neural substrates of focusing on emotional attributes of words in normal subjects. The key findings were that responding to targets defined on the basis of meaning of words compared to targets defined on the basis of perceptual features was associated with response in inferior frontal gyrus and dorsal anterior cingulate. Further, selecting emotional targets, whether happy or sad, was associated with enhanced response in the subgenual cingulate, while happy targets elicited enhanced neural response in ventral anterior cingulate. These findings reaffirm the importance of medial prefrontal regions in normal emotional processing.

A rare coding variant within the wolframin gene in bipolar and unipolar affective disorder cases.

A recent report has shown that Wolfram syndrome carriers (heterozygotes) are 26-fold more likely to require psychiatric hospitalization compared with non-carriers, and that Wolfram syndrome heterozygotes may constitute approximately 25% of individuals hospitalized with depression and suicide attempts. We analyzed a His611Arg polymorphism of the wolframin gene by the polymerase chain reaction (PCR) and HhaI restriction digestion, in 158 bipolar I and 163 unipolar major affective disorder cases, and 316 controls. Statistical analyses of allele or genotype frequencies do not support a major role for wolframin in affective disorder. HhaI restriction digestion and sequencing of PCR products from four affective disorder cases showed a heterozygous Ala559Thr change. The Ala559Thr variant was not detectable in 382 controls tested. Thus, the rare wolframin 559Thr allele deserves consideration as a risk allele for affective disorder.

Ecologically valid cognitive tests and everyday functioning in euthymic bipolar disorder patients.

BACKGROUND: In euthymic bipolar disorder patients, scores on the Mini-Mental State Examination (MMSE) are not abnormal but general functioning remains impaired. Recent studies provide ample evidence that euthymic patients show significant impairment on more comprehensive neuropsychological test batteries. There is no definitive relationship between performance on neuropsychological test batteries and the ability to cope in everyday life. Ecologically valid tests of cognitive function aim to bridge this gap as they use everyday tasks to explore cognitive function. The aims of the study were to examine if euthymic bipolar disorder patients were impaired on ecologically valid tests of cognitive function and measures of general, social and occupational function. We examined the relationships between cognitive impairment and residual symptoms, clinical history, general functioning and employment. METHOD: Cognitive tasks, functional assessments and mood scales were administered to 29 euthymic bipolar disorder patients and 29 matched controls. RESULTS: Patients were impaired on ecologically valid tests of attention, memory and executive function. Patients showed impairment in general, social and occupational functioning. Unemployment was associated with impairment in attention. Memory impairment correlated with number of previous manic episodes. LIMITATIONS: All patients were on psychotropic medication, which may affect cognition. Traditional neuropsychological tests were not performed concurrently with ecologically valid tests. CONCLUSIONS: Ecologically valid tests of cognitive function are sensitive in detecting cognitive impairment in euthymic bipolar disorder. Clinicians should consider using these tests in the recovery phase of bipolar illness, as they may be particularly helpful in showing where rehabilitation should focus.

Impaired cognition and decision-making in bipolar depression but no 'affective bias' evident.

BACKGROUND: Depression is usually the predominant affective state in bipolar disorder. There are few studies, with discrepant views, examining the extent of cognitive impairment in patients with bipolar depression. To our knowledge, there are no previous studies examining decision-making ability or whether there is an affective attentional bias in bipolar depression. METHOD: We ascertained 24 depressed bipolar I patients from acute psychiatric hospital wards and out-patient clinics and 26 age- and IQ-matched healthy controls. Using computerized tests we evaluated their performance on 'neutral' (non-emotional) cognitive tasks (i.e. memory, attention and executive function) and on novel tasks of emotional cognition (i.e. the decision-making task and the affective go/no-go task). RESULTS: Accuracy measures were significantly impaired on tests of visual and spatial recognition and attentional set-shifting in bipolar depression compared with age- and IQ-matched controls. The quality of decision-making was also significantly impaired in the patients. A mood-congruent attentional bias for 'sad' targets was not evident on the affective go/no-go task. CONCLUSIONS: We found widespread evidence of significant cognitive impairment and impaired quality of decision-making in symptomatically severe depressed bipolar patients. This cognitive impairment may contribute to difficulties with daily living, decision-making and the ability to engage and comply with psychological and drug treatments.

Mild myotonic dystrophy is associated with memory impairment in the context of normal general intelligence.

Previous investigations of cognitive function in myotonic dystrophy (DM) suggested that DM subjects have impairment of general intelligence and severe defects in executive function. These studies had to neglect patients with mild clinical disease, since they were generally performed before the availability of DNA testing for DM. We have investigated a group of milder DM cases (defined both by their degree of disability and CTG expansion size) and have not found any defect in general intelligence using the National Adult Reading Test, Standard Progressive Matrices, and Mini-Mental State examination. Three executive function tests were used. The cognitive estimates test and the Wisconsin Card Sorting Test showed tendencies towards impairment, which were of borderline significance, but the verbal fluency task was performed normally. However, in the face of normal general intelligence, mild DM subjects as a group show impairment of memory function. This suggests that memory function may be more sensitive to small CTG repeat expansions than general intelligence.

Cognitive impairment in remission in bipolar affective disorder.

BACKGROUND: Although the traditional view of bipolar affective disorder is that the majority of patients have full remission between episodes, recent evidence suggests that residual cognitive deficits are present. The aim of this study was to determine whether memory and executive deficits were present in a well-defined clinically remitted group of patients. METHODS: This was a case-control study of bipolar patients in remission (N = 18). Subjects had to fulfil stringent clinical criteria for inclusion into the study and had to have been in remission for at least 4 months. Subjects also had no history of substance dependence. The cognitive battery examined memory and executive function. RESULTS: Patients in excellent clinical remission and who reported good social adaptation showed imipairment on tests of visuospatial recognition memory. Accuracy on four tests of executive function was not impaired in patients in remission compared with controls, although response latency on these executive tests was still impaired. CONCLUSIONS: As our group and others have shown, patients with mania and unipolar depression show generalized impairment on tests of memory and executive function. In comparison, this study has demonstrated that patients in remission show a relatively specific impairment in memory with recovery of accuracy measures on executive function task. The increased response latency on the executive tasks suggests a possible small residual impairment. These findings suggest that in netIroanatomical terms, more posterior cortical function (temporal lobe) has not improved but there is at least some recovery of frontal lobe function in remission.

Apathy and hypersomnia are common features of myotonic dystrophy.

OBJECTIVES: Myotonic dystrophy is a disease characterised by myotonia and muscle weakness. Psychiatric disorder and sleep problems have also been considered important features of the illness. This study investigated the extent to which apathy, major depression, and hypersomnolence were present. The objective was to clarify if the apathy reported anecdotally was a feature of CNS involvement or if this was attributable to major depression, hypersomnolence, or a consequence of chronic muscle weakness. METHODS: These features were studied in 36 adults with non-congenital myotonic dystrophy and 13 patients with Charcot-Marie-Tooth disease. By using patients with Charcot-Marie-Tooth disease as a comparison group the aim was to control for the disabling effects of having an inherited chronic neurological disease causing muscle weakness. Standardised assessment instruments were used wherever possible to facilitate comparison with other groups reported in the medical literature. RESULTS: There was no excess of major depression on cross sectional analysis in these patients with mild myotonic dystrophy. However, apathy was a prominent feature of myotonic dystrophy in comparison with a similarly disabled group of patients with Charcot-Marie-Tooth disease (clinician rated score; Mann Whitney U test, p=0.0005). Rates of hypersomnolence were greater in the myotonic dystrophy group, occurring in 39% of myotonic dystrophy patients, but there was no correlation with apathy. CONCLUSION: These data suggest that apathy and hypersomnia are independent and common features of myotonic dystrophy. Apathy cannot be accounted for by clinical depression or peripheral muscle weakness and is therefore likely to reflect CNS involvement. These features of the disease impair quality of life and may be treatable.

Decision-making in mania: a PET study.

Poor decision-making is often observed clinically in the manic syndrome. In normal volunteers, decision-making has been associated with activation in the ventral prefrontal cortex and the anterior cingulate gyrus. The aim of this study was to evaluate task-related activation in bipolar manic patients in these regions of the prefrontal cortex using PET. Six subjects with mania, 10 controls and six subjects with unipolar depression (an affective patient control group) were scanned using the bolus H(2)(15)O method while they were performing a decision-making task. Activations associated with the decision-making task were observed at two levels of difficulty. Task-related activation was increased in the manic patients compared with the control patients in the left dorsal anterior cingulate [Brodmann area (BA) 32] but decreased in the right frontal polar region (BA 10). In addition, controls showed greater task-related activation in the inferior frontal gyrus (BA 47) than manic patients. A positive correlation (r(s) = 0.88) between task-related activation in the anterior cingulate and increasing severity of manic symptoms was found. Depressed patients did not show significant task-related differences in activation compared with control subjects in the regions of interest. In conclusion, these patterns of activation point to abnormal task-related responses in specific frontal regions in manic patients. Moreover, they are consistent with neuropsychological observations in patients with lesions in the ventromedial prefrontal cortex, who show similar difficulties with decision-making and provide early evidence for context-specific neural correlates of mania.

Decision-making cognition in mania and depression.

BACKGROUND: Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. Recent work has suggested that differences may emerge on cognitive tasks requiring affective processing, such as decision-making. The present study sought to compare decision-making cognition in mania and depression in order to clarify the current profiles of impairment for these disorders and to contribute to our more general understanding of the relationship between mood and cognition. METHODS: Medicated manic patients, depressed patients, and normal healthy controls completed a computerized decision-making task. All subjects were asked to win as many points as possible by choosing outcomes based on variably-weighted probabilities and by placing 'bets' on each decision. RESULTS: Both patient groups were impaired on this task, as evidenced by slower deliberation times, a failure to accumulate as many points as controls and suboptimal betting strategies. Manic, but not depressed, patients made suboptimal decisions--an impairment that correlated with the severity of their illness. CONCLUSIONS: These findings are consistent with a growing consensus that manic and depressed patients are characterized by significant impairments in cognitive and particularly executive, functioning. Furthermore, the distinct patterns of observed impairment in manic and depressed patients suggests that the nature and extent of cognitive impairment differ between these two groups. Viewed in the context of other recent studies, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood-cognition relationships.

Mitochondrial genetic analyses suggest selection against maternal lineages in bipolar affective disorder.

Previous reports of preferential transmission of bipolar affective disorder (BP) from the maternal versus the paternal lines in families suggested that this disorder may be caused by mitochondrial DNA mutations. We have sequenced the mitochondrial genome in 25 BP patients with family histories of psychiatric disorder that suggest matrilineal inheritance. No polymorphism identified more than once in this sequencing showed any significant association with BP in association studies using 94 cases and 94 controls. To determine whether our BP sample showed evidence of selection against the maternal lineage, we determined genetic distances between all possible pairwise comparisons within the BP and control groups, based on multilocus mitochondrial polymorphism haplotypes. These analyses revealed fewer closely related haplotypes in the BP group than in the matched control group, suggesting selection against maternal lineages in this disease. Such selection is compatible with recurrent mitochondrial mutations, which are associated with slightly decreased fitness. Although such mismatch distribution comparisons have been used previously for analyses of population histories, this is, as far as we are aware, the first report of this method being used to study disease.

Emotional bias and inhibitory control processes in mania and depression.

BACKGROUND: Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. The disinhibited behaviour characteristic of mania and evidence that subgenual prefrontal cortex is differentially activated in mania and depression both suggest that dissociable deficits will emerge on tasks that require inhibitory control and are subserved by ventromedial prefrontal cortex. METHODS: Manic patients and controls undertook computerized neuropsychological tests of memory and planning ability. In addition, manic and depressed patients were directly compared with controls on a novel affective shifting task that requires inhibitory control over different components of cognitive and emotional processing. RESULTS: Manic patients were impaired on tests of memory and planning. Importantly, affective shifting performance of manic patients differed from that of depressed patients. Manic patients were impaired in their ability to inhibit behavioural responses and focus attention, but depressed patients were impaired in their ability to shift the focus of attention. Depressed patients exhibited an affective bias for negative stimuli, and we believe this to be the first demonstration of an affective bias for positive stimuli in manic patients. CONCLUSIONS: Observed impairments on tests of memory and planning suggest a global pathology for mania consistent with previous profiles for this disorder and similar to established profiles for depression. The results on the affective shifting task demonstrate the presence of mood-congruent bias and dissociable components of inhibitory control in mania and depression. Against a background of memory and planning impairments in the two groups, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood-cognition relationships.